Angiotensin 2 for Hepatorenal Syndrome (ANTHEM)

Angiotensin 2 as a Novel Treatment for Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a disease in which patients with cirrhosis (end stage liver failure) develop secondary kidney injury and failure. The current treatment available in the United States is a combination of octreotide and midodrine, which are meant to decrease the release of those hormones and raise the blood pressure, respectively, which would increase blood flow to the kidneys. Angiotensin 2 (Ang2) is a new vasopressor drug that was approved by the FDA in December 2017 for patients with low blood pressure and has been shown to have similar effects to octreotide and midodrine.

This study will investigate whether Ang2 reverses HRS among patients admitted to the intensive care unit (ICU) at Ronald Reagan Medical Center. Our study population will be patients with HRS who are already or will be admitted to the ICU. HRS will be defined by new internationally accepted guidelines published by the International Club of Ascites. All patients who are consented will undergo an Ang2 response trial, where low-dose Ang2 will be administered for 4 hours to see how the patients respond. This will help us characterize the nature of the patients' kidney failure for later analysis. Patients will then be randomized into the control group or the study group. Patients in the control group will receive octreotide (a subcutaneous injection) and midodrine (an oral drug). Patients in the study group will continue receiving intravenous infusion of Ang2. Patients in both groups will also receive albumin, a protein found commonly in human blood. Treatment will continue in both groups for four days, until complete reversal of HRS, dialysis, or death.

Our primary outcome will be rate of reversal of HRS, defined as improvement in kidney function.

Study Overview

• Status: Withdrawn
• Conditions: Cirrhosis; Kidney Failure, Acute; Hepatorenal Syndrome
• Intervention / Treatment: Drug: Midodrine; Drug: Octreotide; Drug: Albumin solution; Drug: Angiotensin II

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Y Lin, MD; Phone Number: 3102678678; Email: mylin@mednet.ucla.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Patients in the ICU with HRS-AKI defined as

• Acute kidney injury defined as an increase in serum creatinine (sCr) >=0.3 mg/dl or >=50% from baseline within 7 days
• Presence of cirrhosis and ascites
• Absence of other causes such as shock, nephrotoxic drugs, or other suspected causes of kidney injury.
• Lack of response to diuretic withdrawal and albumin challenge of 1 g/kg of body weight

Exclusion Criteria:

• Age <18 years
• Current or anticipated (within 24 hours) need for renal replacement therapy (RRT)
• Cr > 6 mg/dl
• Renal transplantation status
• Fractional Excretion of Sodium (FeNa) > 2%
• Pregnancy
• Recent Cerebrovascular Accident (CVA), Myocardial Infarction (MI), venous or arterial thrombosis (within last 3 months)
• Known hypercoagulable state other than cirrhosis
• Uncontrolled hypertension (SBP > 160)
• Anticipated mortality within 72 hours
• Inability to obtain consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Midodrine/Octreotide; This arm will receive standard of care treatment of midodrine, octreotide, and albumin.	Drug: Midodrine; Pill; Drug: Octreotide; Subcutaneous; Drug: Albumin solution; Intravenous suspension
Experimental: Angiotensin 2; This arm will receive the experimental treatment of angiotensin 2 infusion and albumin.	Drug: Albumin solution; Intravenous suspension; Drug: Angiotensin II; Intravenous; Other Names: Giapreza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reversal of hepatorenal syndrome	Partial or complete reversal of HRS. Serum creatinine will be measured daily and compared against the patient's baseline creatinine. Partial reversal is defined defined as improvement of at least one AKI stage as defined by International Club of Ascites Acute Kidney Injury (ICA-AKI) criteria Complete defined as improvement of serum creatinine to within 0.3 mg/dl of baseline value). ICA-AKI criteria: Stage 1: increase in sCr ≥0.3 mg/dl (26.5 μmol/L) or an increase in sCr ≥1.5-fold to 2-fold from baseline; Stage 2: increase in sCr >2-fold to 3-fold from baseline; Stage 3: increase of sCr >3-fold from baseline or sCr ≥4.0 mg/dl (353.6 μmol/L) with an acute increase ≥0.3 mg/dl (26.5 μmol/L) or initiation of renal replacement therapy Angeli P et al. J Hepatology 2015:62(968-974)	4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for renal replacement therapy	The treating team with the assistance of nephrology will assess the acute need for dialysis on a daily basis. If the patient does require urgent hemodialysis at their determination, this will be noted. The proportion of each group who required hemodialysis will be compared.	4 days
Mortality	In-hospital mortality	28 days
Serum sodium	Change in serum sodium from the beginning of the study to the end of the study.	4 days
Relapse of hepatorenal syndrome	Recurrence of HRS-AKI after withdrawal of study drug, defined as a worsening of AKI by at least one stage according to ICA-AKI criteria AKI grade as defined by ICA-AKI criteria (J Hepatology 2015:62[968-974])	14 days

Collaborators and Investigators

• Sponsor: University of California, Los Angeles

Publications and helpful links

General Publications

• Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, Kashani K, Szerlip HM, Prowle JR, Bihorac A, Finkel KW, Zarbock A, Forni LG, Lynch SJ, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Bellomo R; Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. Crit Care Med. 2018 Jun;46(6):949-957. doi: 10.1097/CCM.0000000000003092. Erratum In: Crit Care Med. 2018 Aug;46(8):e824.
• Khanna A, Ostermann M, Bellomo R. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Dec 28;377(26):2604. doi: 10.1056/NEJMc1714511. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2021
• Primary Completion (Estimated): June 30, 2023
• Study Completion (Estimated): July 1, 2023

Study Registration Dates

• First Submitted: July 29, 2019
• First Submitted That Met QC Criteria: August 5, 2019
• First Posted (Actual): August 7, 2019

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Renal Insufficiency; Acute Kidney Injury; Hepatorenal Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Protease Inhibitors; Adrenergic alpha-Agonists; Adrenergic Agonists; Serine Proteinase Inhibitors; Sympathomimetics; Vasoconstrictor Agents; Adrenergic alpha-1 Receptor Agonists; Octreotide; Midodrine; Angiotensin II; Giapreza; Angiotensinogen
• Other Study ID Numbers: #19-005718

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes